melphalan and Chemical-and-Drug-Induced-Liver-Injury

Topics: Chemical and Drug Induced Liver Injury; Databases, Factual; Drug Labeling; Humans; Pharmaceutical Preparations; Risk

Drug-induced liver injury (DILI) is a leading cause of liver failure and an important safety issue in drug development. Thalidomide is nowadays used for the treatment of several conditions including multiple myeloma (MM). Several adverse effects have been described but liver toxicity was seldom reported. We describe a case of thalidomide-induced hepatitis in a man treated for MM. The clinical setting and temporal association between the start of the drug and liver injury allowed the assumption of the causative role of thalidomide. As its clinical indications expand we wish to increase awareness of a new potential side effect of thalidomide. A short review on thalidomide-induced liver injury is also presented.

Topics: Acute Disease; Aged; Antineoplastic Combined Chemotherapy Protocols; Biopsy; Chemical and Drug Induced Liver Injury; Darbepoetin alfa; Diazepam; Erythropoietin; Fatal Outcome; Humans; Jaundice, Obstructive; Liver Function Tests; Male; Melphalan; Multiple Myeloma; Omeprazole; Pneumonia; Polypharmacy; Prednisolone; Thalidomide

The current study was designed to assess the safety and efficacy of bortezomib in combination with fludarabine and melphalan as reduced intensity conditioning before allogeneic stem cell transplantation in patients with high risk multiple myeloma. Sixteen patients were evaluable. The median number of previous line of treatment was 3; all patients had relapsed following a prior autograft and 13 had previously received bortezomib. Fifteen of them either remained stable or improved disease status at day +100 post-transplant, including 11 patients with active disease. More specifically, nine patients (56%) and five patients (31%) reached complete remission and partial response, respectively. 25% developed grade III acute graft-versus-host disease. The cumulative incidence of non-relapse mortality, relapse and overall survival were 25%, 54% and 41%, respectively, at 3 years. Regarding the non-haematological toxicity (grade>2), two patients developed peripheral neuropathy, two patients liver toxicity and 1 pulmonary toxicity early post-transplant. The haematological toxicity was only observed during the first three cycles mostly related to low haemoglobin and platelet levels. The current trial is the first one evaluating the safety and efficacy of bortezomib as part of a reduced intensity conditioning regimen among patients with high risk multiple myeloma.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Boronic Acids; Bortezomib; Chemical and Drug Induced Liver Injury; Combined Modality Therapy; Cyclosporine; Drug Synergism; Female; Graft vs Host Disease; Hematologic Diseases; Humans; Immunosuppressive Agents; Maintenance Chemotherapy; Male; Melphalan; Middle Aged; Multiple Myeloma; Peripheral Blood Stem Cell Transplantation; Peripheral Nervous System Diseases; Protease Inhibitors; Pyrazines; Remission Induction; Reoperation; Salvage Therapy; T-Lymphocyte Subsets; Transplantation Conditioning; Transplantation, Autologous; Transplantation, Homologous; Vidarabine

Autologous stem cell transplantation after high-dose melphalan for the treatment with multiple myeloma has resulted in prolonged progression-free survival and overall survival in patients under 65 years. We have examined the role of autologous transplantation in 17 patients with multiple myeloma over 65 years at our centre using a matched pair analysis with younger patients. The median age of this cohort of patients over 65 years was 67 years (65-74) and their outcome and transplant-related morbidity was compared with 17 younger pair mates with a median age of 55 years (31-64). Sixteen patients received high-dose melphalan, and one received busulphan with autologous stem cell rescue. The high-dose therapy was well tolerated in both elderly patients and the matched pairs, with comparable time to recover neutrophils and platelets. Treatment-related mortality also did not differ significantly in both the groups. Median overall survival of the elderly patients was 3.59 years similar to 3.01 years of the pair mates (P = 0.92). Autologous stem cell transplantation after high-dose melphalan conditioning was equally well tolerated in groups of patients above and below 65 years. There was no difference in relapse rate, OS and myelotoxicity in both the groups. These findings suggest that advanced age should not be an exclusion criterion from autologous transplant programmes. Bone Marrow Transplantation (2000) 25, 533-539.

Topics: Adult; Age Factors; Aged; Antineoplastic Combined Chemotherapy Protocols; Busulfan; Carmustine; Chemical and Drug Induced Liver Injury; Cohort Studies; Cyclophosphamide; Disease-Free Survival; Doxorubicin; Female; Graft Survival; Heart Diseases; Hematopoietic Stem Cell Mobilization; Hospitalization; Humans; Interferons; Kidney Diseases; Male; Matched-Pair Analysis; Melphalan; Methylprednisolone; Middle Aged; Multiple Myeloma; Neutropenia; Neutrophils; Platelet Count; Recurrence; Sepsis; Survival Rate; Thrombocytopenia; Transplantation, Autologous; Vincristine

The matrix protein tenascin-C (TN-C) is present in the blood of healthy individuals at concentrations around 1 mg/l. Elevated serum levels have been reported in cancer patients. In this study we have measured the concentration of circulating TN-C in 40 patients with melanoma, soft-tissue sarcoma (STS) or squamous-cell carcinoma (SCC) of the limbs, and have found a minor increase in the mean concentration compared with healthy subjects. Only 10 patients had TN-C levels above the normal range. No correlation was observed between TN-C levels and tumor burden. Nineteen patients were treated by isolation limb perfusion (ILP) with TNF, IFN gamma, melphalan (11 melanoma, 2 SCC and I STS), melphalan alone (3 melanoma) or hyperthermia at 41.5 degrees C (2 melanoma). ILP with TNF, IFN gamma and melphalan induced a rapid increase in plasma TN-C levels, peaking in most patients between 24 or 48 hr after ILP. Two patients treated with hyperthermia only had a slow increase in TN-C concentration peaking at day 4, while the patients treated with melphalan alone had no significant change. In some cases elevated TN-C levels persisted for over 8 weeks after ILP. The early rise in TN-C concentration correlates with the increase in circulating C-reactive protein. Our findings suggest that circulating TN-C behaves, at least in part, as an acute-phase protein and that it may play a role in the inflammatory response.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Blood Platelets; C-Reactive Protein; Carcinoma, Squamous Cell; Chemical and Drug Induced Liver Injury; Chemotherapy, Cancer, Regional Perfusion; Dose-Response Relationship, Drug; Extremities; Female; Humans; Interferon-gamma; Interleukin-6; Male; Melanoma; Melphalan; Middle Aged; Neoplasms; Recombinant Proteins; Sarcoma; Soft Tissue Neoplasms; Tenascin; Tumor Necrosis Factor-alpha

The bile salt export pump (BSEP) is expressed at the canalicular domain of hepatocytes, where it serves as the primary route of elimination for monovalent bile acids (BAs) into the bile canaliculi. The most compelling evidence linking dysfunction in BA transport with liver injury in humans is found with carriers of mutations that render BSEP nonfunctional. Based on mounting evidence, there appears to be a strong association between drug-induced BSEP interference and liver injury in humans; however, causality has not been established. For this reason, drug-induced BSEP interference is best considered a susceptibility factor for liver injury as other host- or drug-related properties may contribute to the development of hepatotoxicity. To better understand the association between BSEP interference and liver injury in humans, over 600 marketed or withdrawn drugs were evaluated in BSEP expressing membrane vesicles. The example of a compound that failed during phase 1 human trials is also described, AMG 009. AMG 009 showed evidence of liver injury in humans that was not predicted by preclinical safety studies, and BSEP inhibition was implicated. For 109 of the drugs with some effect on in vitro BSEP function, clinical use, associations with hepatotoxicity, pharmacokinetic data, and other information were annotated. A steady state concentration (C(ss)) for each of these annotated drugs was estimated, and a ratio between this value and measured IC₅₀ potency values were calculated in an attempt to relate exposure to in vitro potencies. When factoring for exposure, 95% of the annotated compounds with a C(ss)/BSEP IC₅₀ ratio ≥ 0.1 were associated with some form of liver injury. We then investigated the relationship between clinical evidence of liver injury and effects to multidrug resistance-associated proteins (MRPs) believed to play a role in BA homeostasis. The effect of 600+ drugs on MRP2, MRP3, and MRP4 function was also evaluated in membrane vesicle assays. Drugs with a C(ss)/BSEP IC₅₀ ratio ≥ 0.1 and a C(ss)/MRP IC₅₀ ratio ≥ 0.1 had almost a 100% correlation with some evidence of liver injury in humans. These data suggest that integration of exposure data, and knowledge of an effect to not only BSEP but also one or more of the MRPs, is a useful tool for informing the potential for liver injury due to altered BA transport.

Topics: Animals; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 11; ATP-Binding Cassette Transporters; Biological Transport; Chemical and Drug Induced Liver Injury; Cluster Analysis; Drug-Related Side Effects and Adverse Reactions; Humans; Liver; Male; Multidrug Resistance-Associated Proteins; Pharmacokinetics; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Risk Assessment; Risk Factors; Toxicity Tests

The human bile salt export pump (BSEP) is a membrane protein expressed on the canalicular plasma membrane domain of hepatocytes, which mediates active transport of unconjugated and conjugated bile salts from liver cells into bile. BSEP activity therefore plays an important role in bile flow. In humans, genetically inherited defects in BSEP expression or activity cause cholestatic liver injury, and many drugs that cause cholestatic drug-induced liver injury (DILI) in humans have been shown to inhibit BSEP activity in vitro and in vivo. These findings suggest that inhibition of BSEP activity by drugs could be one of the mechanisms that initiate human DILI. To gain insight into the chemical features responsible for BSEP inhibition, we have used a recently described in vitro membrane vesicle BSEP inhibition assay to quantify transporter inhibition for a set of 624 compounds. The relationship between BSEP inhibition and molecular physicochemical properties was investigated, and our results show that lipophilicity and molecular size are significantly correlated with BSEP inhibition. This data set was further used to build predictive BSEP classification models through multiple quantitative structure-activity relationship modeling approaches. The highest level of predictive accuracy was provided by a support vector machine model (accuracy = 0.87, κ = 0.74). These analyses highlight the potential value that can be gained by combining computational methods with experimental efforts in early stages of drug discovery projects to minimize the propensity of drug candidates to inhibit BSEP.

Topics: Animals; ATP Binding Cassette Transporter, Subfamily B, Member 11; ATP-Binding Cassette Transporters; Bile Acids and Salts; Cell Line; Chemical and Drug Induced Liver Injury; Humans; Quantitative Structure-Activity Relationship

Drug-induced liver injury (DILI) is a significant concern in drug development due to the poor concordance between preclinical and clinical findings of liver toxicity. We hypothesized that the DILI types (hepatotoxic side effects) seen in the clinic can be translated into the development of predictive in silico models for use in the drug discovery phase. We identified 13 hepatotoxic side effects with high accuracy for classifying marketed drugs for their DILI potential. We then developed in silico predictive models for each of these 13 side effects, which were further combined to construct a DILI prediction system (DILIps). The DILIps yielded 60-70% prediction accuracy for three independent validation sets. To enhance the confidence for identification of drugs that cause severe DILI in humans, the "Rule of Three" was developed in DILIps by using a consensus strategy based on 13 models. This gave high positive predictive value (91%) when applied to an external dataset containing 206 drugs from three independent literature datasets. Using the DILIps, we screened all the drugs in DrugBank and investigated their DILI potential in terms of protein targets and therapeutic categories through network modeling. We demonstrated that two therapeutic categories, anti-infectives for systemic use and musculoskeletal system drugs, were enriched for DILI, which is consistent with current knowledge. We also identified protein targets and pathways that are related to drugs that cause DILI by using pathway analysis and co-occurrence text mining. While marketed drugs were the focus of this study, the DILIps has a potential as an evaluation tool to screen and prioritize new drug candidates or chemicals, such as environmental chemicals, to avoid those that might cause liver toxicity. We expect that the methodology can be also applied to other drug safety endpoints, such as renal or cardiovascular toxicity.

Topics: Animals; Anti-Infective Agents; Anti-Inflammatory Agents; Chemical and Drug Induced Liver Injury; Databases, Factual; Drug-Related Side Effects and Adverse Reactions; Humans; Liver; Models, Biological; Predictive Value of Tests

Drug-induced liver injury is one of the main causes of drug attrition. The ability to predict the liver effects of drug candidates from their chemical structures is critical to help guide experimental drug discovery projects toward safer medicines. In this study, we have compiled a data set of 951 compounds reported to produce a wide range of effects in the liver in different species, comprising humans, rodents, and nonrodents. The liver effects for this data set were obtained as assertional metadata, generated from MEDLINE abstracts using a unique combination of lexical and linguistic methods and ontological rules. We have analyzed this data set using conventional cheminformatics approaches and addressed several questions pertaining to cross-species concordance of liver effects, chemical determinants of liver effects in humans, and the prediction of whether a given compound is likely to cause a liver effect in humans. We found that the concordance of liver effects was relatively low (ca. 39-44%) between different species, raising the possibility that species specificity could depend on specific features of chemical structure. Compounds were clustered by their chemical similarity, and similar compounds were examined for the expected similarity of their species-dependent liver effect profiles. In most cases, similar profiles were observed for members of the same cluster, but some compounds appeared as outliers. The outliers were the subject of focused assertion regeneration from MEDLINE as well as other data sources. In some cases, additional biological assertions were identified, which were in line with expectations based on compounds' chemical similarities. The assertions were further converted to binary annotations of underlying chemicals (i.e., liver effect vs no liver effect), and binary quantitative structure-activity relationship (QSAR) models were generated to predict whether a compound would be expected to produce liver effects in humans. Despite the apparent heterogeneity of data, models have shown good predictive power assessed by external 5-fold cross-validation procedures. The external predictive power of binary QSAR models was further confirmed by their application to compounds that were retrieved or studied after the model was developed. To the best of our knowledge, this is the first study for chemical toxicity prediction that applied QSAR modeling and other cheminformatics techniques to observational data generated by the means of automate

Topics: Animals; Chemical and Drug Induced Liver Injury; Cluster Analysis; Databases, Factual; Humans; MEDLINE; Mice; Models, Chemical; Molecular Conformation; Quantitative Structure-Activity Relationship

In the present work, we report on the results of our pilot study of hyperthermic isolated hepatic perfusion (IHP) with melphalan alone for patients with unresectable metastatic liver tumors refractory to conventional treatments, with particular regard to the correlation between pharmacokinetic findings and hepatic toxicity.. Inclusion criteria were unresectable liver metastases, hepatic parenchyma replacement

Topics: Adult; Aged; Antineoplastic Agents, Alkylating; Chemical and Drug Induced Liver Injury; Chemotherapy, Cancer, Regional Perfusion; Feasibility Studies; Female; Humans; Hyperthermia, Induced; Liver Neoplasms; Male; Melphalan; Middle Aged; Pilot Projects

Liver injury is a common complication in allogeneic hematopoietic stem cell transplantation. Its major causes comprise graft-versus-host disease (GVHD), infection, and toxicities of preparative regimens and immunosuppressants; however, we have little information on liver injuries after reduced intensity cord blood transplantation (RICBT). We reviewed medical records of 104 recipients who underwent RICBT between March 2002 and May 2004 at Toranomon Hospital. Preparative regimen and GVHD prophylaxis comprised fludarabine/melphalan/total body irradiation and cyclosporine or tacrolimus. We assessed the etiology of liver injuries based on the clinical presentation, laboratory results, comorbid events, and imaging studies in 85 patients who achieved primary engraftment. The severity of liver dysfunction was assessed according to the National Cancer Institute Common Toxicity Criteria version 2.0. Hyperbilirubinemia was graded according to a report by Hogan et al (Blood. 2004;103:78-84). Moderate to very severe liver injuries were observed in 36 patients. Their causes included cholestatic liver disease (CLD) related to GVHD or sepsis (n = 15), GVHD (n = 7), cholangitis lenta (n = 5), and others (n = 9). Median onsets of CLD, GVHD, and cholangitis lenta were days 37, 40, and 22, respectively. Frequencies of grade 3-4 alanine aminotransferase elevation were comparable across the 3 types of hepatic injuries. Serum gamma-glutamil transpeptidase was not elevated in any patients with cholangitis lenta, whereas 27% and 40% of patients with CLD and GVHD, respectively, developed grade 3-4 gamma-glutamil transpeptidase elevation. Multivariate analysis identified 2 risk factors for hyperbilirubinemia; grade II-IV acute GVHD (relative risk, 2.23; 95% confidential interval, 1.11-4.47; P = .024) and blood stream infection (relative risk, 3.77; 95% confidential interval, 1.91-7.44; P = .00013). In conclusion, the present study has demonstrated that the hepatic injuries are significant problems after RICBT, and that GVHD and blood stream infection contribute to their pathogenesis.

Topics: Adolescent; Adult; Aged; Anti-Bacterial Agents; Bacterial Infections; Busulfan; Chemical and Drug Induced Liver Injury; Cholangitis; Cord Blood Stem Cell Transplantation; Cyclosporine; Female; Hematologic Diseases; Hematologic Neoplasms; Hepatic Veno-Occlusive Disease; Humans; Hyperbilirubinemia; Immunosuppressive Agents; Incidence; Infant, Newborn; Liver Diseases; Liver Function Tests; Male; Melphalan; Middle Aged; Postoperative Complications; Risk Factors; Tacrolimus; Tissue Donors; Transplantation Conditioning; Vidarabine; Whole-Body Irradiation

Isolated hepatic perfusion of nonresectable liver cancer using the combination of TNF and melphalan can be associated with a treatment-related hepatotoxicity. We investigated whether, apart from TNF, also melphalan is cytotoxic in primary murine liver cells in vitro and investigated mediators, mode of cell death, and cell types involved. Melphalan induced a caspase-dependent apoptosis in hepatocytes, which was not seen in liver cell preparations depleted of Kupffer cells. Neutralization of TNF prevented melphalan-induced apoptosis and liver cells derived from mice genetically deficient in either TNFR 1 or 2, but not from lpr mice lacking a functional CD95 receptor, were completely resistant. Cell-cell contact between hepatocytes and Kupffer cells was required for apoptosis to occur. Melphalan increased membrane-bound but not secreted TNF in Kupffer cells and inhibited recombinant TNF-alpha converting enzyme in vitro. Melphalan induced also severe hepatotoxicity in the isolated recirculating perfused mouse liver from wild-type mice but not from TNFR 1 or 2 knockout mice. In conclusion, this study shows that melphalan elicits membrane TNF on Kupffer cells due to inhibition of TNF processing and thereby initiates apoptosis of hepatocytes via obligatory activation of both TNFRs. The identification of this novel mechanism allows a causal understanding of melphalan-induced hepatotoxicity.

Topics: ADAM Proteins; ADAM17 Protein; Animals; Apoptosis; Caspases; Cell Communication; Cells, Cultured; Chemical and Drug Induced Liver Injury; Hepatocytes; Kupffer Cells; Liver Diseases; Male; Melphalan; Membrane Proteins; Mice; Mice, Inbred C57BL; Mice, Knockout; Receptors, Tumor Necrosis Factor, Type I; Receptors, Tumor Necrosis Factor, Type II; Tumor Necrosis Factor-alpha

Hyperthermic antiblastic isolated hepatic perfusion (IHP) with melphalan has been recently proposed as an alternative therapeutic option for patients with unresectable liver tumors. Although melphalan-heat antiblastic synergism is at a maximum at temperatures higher than 41 degrees C, IHP has so far been performed in humans at lower temperatures. In this experimental work, we compared IHP under mild versus true hyperthermic conditions in terms of drug pharmacokinetics and liver function. Ten pigs were submitted to IHP with melphalan 1.5 mg/kg at a mean temperature of 40 degrees C (group A, n = 5) or 42 degrees C (group B, n = 5). After a 60-minute perfusion, a 15-minute washout was performed. Perfusate-to-plasma leakage was monitored using scintigraphy. Throughout perfusion, samples from the systemic blood, perfusate, and liver parenchyma were obtained to measure melphalan concentrations. Liver function was assessed using standard blood tests and the indocyanine green-based test. No deaths related to the IHP procedure were recorded. All animals had transient liver function impairment, with all liver function test results returning to normal within the observation period. At histologic examination, liver damage was similar under both hyperthermic conditions. Melphalan levels in the perfusate were not significantly different in the two study groups (the mean perfusate/plasma area under the curve from 0 to 60 minutes ratios were 463 and 501, respectively). These results correlated well with those obtained using the scintigraphic method. Liver drug concentrations remained unchanged after true hyperthermia IHP. Under true hyperthermic conditions, neither an increase in liver parenchyma toxicity nor changes in melphalan pharmacokinetics were observed. These findings support the use of true hyperthermia in the clinical setting to exploit fully the antitumor synergism between melphalan and heat.

Topics: Animals; Antineoplastic Agents, Alkylating; Chemical and Drug Induced Liver Injury; Chemotherapy, Cancer, Regional Perfusion; Disease Models, Animal; Drug Synergism; Feasibility Studies; Hepatocytes; Hyperthermia, Induced; Liver; Liver Function Tests; Melphalan; Radionuclide Imaging; Swine; Technetium Tc 99m Aggregated Albumin; Temperature

We conducted a pilot study in 20 patients with high-risk or recurrent/refractory non-Hodgkin's lymphoma (NHL) using high-dose sequential chemotherapy (HDSC) and autologous hematopoietic cell transplantation (AHCT). After cytoreduction with standard salvage therapy, HDSC/AHCT was administered in 4 phases at 2- to 4-week intervals. Phase 1 consisted of cyclophosphamide 7 g/m2 followed by granulocyte colony-stimulating factor (G-CSF) at 10 microg/kg per day and leukapheresis upon recovery from white blood cell nadir. The hematopoietic cell product was enriched by Percoll gradient separation and purged with a B-cell or T-cell monoclonal antibody panel and complement. Phase 2 consisted of methotrexate 8 g/m2 with leucovorin rescue and vincristine 1.4 mg/m2. Phase 3 was etoposide 2 g/m2 with G-CSF 5 microg/kg per day. In phase 4, the preparative regimen of mitoxantrone 60 mg/m2 and melphalan 180 mg/m2 was administered followed by AHCT. The NHL histologies were diffuse large cell, follicular/diffuse mixed, small noncleaved cell, T-cell-rich B-cell, lymphoblastic, and peripheral T cell. The remission status was first partial remission (PR1; n = 1) or beyond first complete remission (post-CR1; n = 19). Of the 20 patients enrolled, 11 proceeded through all 4 phases. Nine were removed from the study after the first or second phase because of progressive disease (n = 5), poor hematopoietic cell mobilization (n = 1), excessive toxicity (n = 2), and chronic active hepatitis C (n = 1). Treatment-related toxicities in the remaining 11 transplant recipients were cardiomyopathy, hemorrhagic cystitis, persistent cytopenias, acute renal failure, abnormal liver function test results, and infectious complications. There were no treatment-related deaths. Eight of the 11 transplant recipients were alive, 6 without disease, at a median follow-up of 2.7 years. The estimated median 2-year event-free survival was 55%, and overall survival was 70%. We conclude that HDSC/AHCT in refractory/recurrent NHL is associated with considerable acute and chronic toxicities. Given the toxicity profile, efficacy data were not sufficiently promising to warrant further study.

Topics: Acute Kidney Injury; Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Diseases; Bone Marrow Purging; Cardiomyopathies; Chemical and Drug Induced Liver Injury; Combined Modality Therapy; Cyclophosphamide; Cystitis; Disease Progression; Disease-Free Survival; Drug Administration Schedule; Etoposide; Female; Follow-Up Studies; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cell Transplantation; Hemorrhage; Humans; Infections; Leucovorin; Life Tables; Lymphoma, Non-Hodgkin; Male; Melphalan; Methotrexate; Middle Aged; Mitoxantrone; Pilot Projects; Salvage Therapy; Survival Analysis; Survival Rate; Transplantation Conditioning; Transplantation, Autologous; Treatment Outcome; Vincristine

Isolated limb perfusion with tumour necrosis factor alpha (TNF-alpha) and melphalan is well tolerated and highly effective in irresectable sarcoma and melanoma. No data are available on isolated hepatic perfusion (IHP) with these drugs for irresectable hepatic malignancies. This study was undertaken to assess the feasibility of such an approach by analysing hepatic and systemic toxicity of IHP with TNF-alpha with and without melphalan in pigs. Ten healthy pigs underwent IHP. After vascular isolation of the liver, inflow catheters were placed in the hepatic artery and portal vein, and an outflow catheter was placed in the inferior vena cava (IVC). An extracorporeal veno-venous bypass was used to shunt blood from the lower body and intestines to the heart. The liver was perfused for 60 min with (1) 50 microg kg(-1) TNF-alpha (n = 5), (2) 50 microg kg(-1) TNF-alpha plus 1 mg kg(-1) melphalan (n = 3) or (3) no drugs (n = 2). The liver was washed with macrodex before restoring vascular continuity. All but one pigs tolerated the procedure well. Stable perfusion was achieved in all animals with median perfusate TNF-alpha levels of 5.1 +/- 0.78 x 10(6) pg ml(-1) (+/- s.e.m). Systemic leakage of TNF-alpha from the perfusate was consistently < 0.02%. Following IHP, a transient elevation of systemic TNF-alpha levels was observed in groups 1 and 2 with a median peak level of 23 +/- 3 x 10(3) pg ml(-1) at 10 min after washout, which normalized within 6 h. No significant systemic toxicity was observed. Mild transient hepatotoxicity was seen to a similar extent in all animals, including controls. IHP with TNF-alpha with(out) melphalan in pigs is technically feasible, results in minimal systemic drug exposure and causes minor transient disturbances of liver biochemistry and histology.

Topics: Alanine Transaminase; Animals; Antineoplastic Agents, Alkylating; Aspartate Aminotransferases; Chemical and Drug Induced Liver Injury; L-Lactate Dehydrogenase; Liver; Liver Diseases; Melphalan; Perfusion; Swine; Tumor Necrosis Factor-alpha

This study reports a large cooperative experience in myeloablative therapy and bone marrow rescue undertaken to define better the outcome of children with disseminated neuroblastoma after megatherapy. Between 1984 and 1993, 135 children underwent myeloablative therapy with bone marrow transplantation (BMT) in nine Italian Centres. One hundred and seventeen children received unpurged autologous BMT, five allogeneic BMT and 13 peripheral blood progenitor cells as rescue. Of these 135 children, 57 were in 1st CR, 11 in 2nd or subsequent CR, 42 in 1st PR, and 25 had more advanced disease. Twelve children (9%) died of toxicity, 86 relapsed or progressed at 1-68 months (median 7 months) and 80 of these subsequently died of progressive disease. Forty-three children are still alive with 37 in continuous remission at a median of 65 months (30-123 months) after BMT. Overall and disease-free survival at 8 years are 28.5% (s.e. 4.3) and 26% (s.e. 4), respectively. Disease-free survival is 34.6% (s.e. 6.7) for the patients grafted in 1st complete remission, 23.6% (s.e. 6.6) for patients grafted in 1st partial remission, 36.4% (s.e. 14.5) for patients grafted in 2nd or subsequent CR, and 8% (5.4) for patients with advanced disease. We conclude these data confirm that early toxicity of myeloablative therapy is manageable and that myeloablative therapy with bone marrow rescue may contribute to an improved long-term survival of children with disseminated neuroblastoma but the objective of cure of all patients remains distant.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Chemical and Drug Induced Liver Injury; Child; Child, Preschool; Combined Modality Therapy; Disease-Free Survival; Female; Humans; Infant; Infant, Newborn; Infections; Italy; Liver Diseases; Male; Melphalan; Neuroblastoma; Registries; Survival Analysis; Survival Rate; Transplantation Conditioning; Treatment Outcome; Vincristine; Whole-Body Irradiation